Liver Cancer Stem Cell Markers (CD133(+)/CD44(+)) Are Strongly Associated With Moderate to Poorly Differentiated Hepatocellular Carcinoma in Patients Undergoing Transplantation.

Purpose: To determine factors associated with cell differentiation, microvascular invasion (MVI) and alpha-fetoprotein levels (AFP) in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods: Between July 1996 and October 2013, 95 patients were transplanted in our institution for HCC. Immunoflourescence was performed to analyze the presence of liver cancer stem cell markers (CD133, CD44, and CD133/44) on explanted HCC. Results: Seventy seven (81%) of these patients were male and 84 (88%) were older than 50. HCC was incidentally found in 30 patients (31%). Median follow-up was 64 months. Thirteen patients (13%) developed tumor recurrence, which was associated with poor survival (P = 0.008). Overall 1, 3, and 5 year survival rates were 86%, 75% and 64%, respectively. Patients without MVI had significantly better survival of 88%, 82% and 68% compared with patients with MVI at the same time points (P = 0.001). AFP greater than 100mg/dl was strongly associated with the presence of MVI in this series. On multivariable analysis CD133+ tumors were independently associated with higher levels of AFP prior to transplant. The presence of CD133+/CD44+ tumors were significantly associated with moderate to poorly differentiated HCC. Conclusions: AFP>100mg/dl was associated with a 13 fold risk of development of MVI. The presence of the LCSC markers CD133+ alone or the combination CD133+/CD44+ in these tumors are strongly associated with elevated levels of AFP and poorly differentiated HCC, respectively.